HCV infection of humans induces a complex immune response characterized by induction of innate immunity followed by both cell mediated and humoral adaptive immune responses. In -20% of acute HCV Infections, the anti-HCV Immune response controls the infection. Analysis of both human and primate HCV infection indicates that clearance is associated with robust CD4 and CDS T cell responses specific for HCV epitopes. Although the generation of neutralizing humoral responses is also likely important in HCV infection, their ultimate role in clearance remains to be determined. Understanding the mechanisms of immune evasion that allow HCV to develop and maintain chronic infection in the majority of cases is critical to prophylactic and therapeutic vaccine development. HCV has a highly error-prone polymerase with a correspondingly high mutation rate, allowing HCV to rapidly escape developing immune responses. Therefore, complete understanding of the successful immune response to HCV with its mechanisms of evasion and escape from sterilizing immunity requires serial analysis of both HCV sequence and HCV-specific adaptive immune responses from the time of initial infection until outcome is determined. In addition to the technical complexity of specific quantitative analysis of epitope specific T cell and humoral responses, the study of HCV immunity is further complicated by the fact that acute infection is generally asymptomatic and therefore typically not detected. The vast majority of HCV infected patients are therefore diagnosed during their chronic phase, long after the critical immune responses to acute infection are generated. The Center includes a unique cohort of injection drug users followed on a monthly basis, thereby allowing high frequency detection of de novo acute HCV infection and longitudinal evaluation of infection outcome. Thus, the proposed research brings together unique patient resources with leaders in the study of HCV-specific T cell and humoral immune responses and HCV sequence evolution. The combination of cohort and sequence evolution and immunologic expertise make the proposed projects feasible, potentially increasing understanding of human chronic viral infections and enhancing development of immunotherapies.